MRSA VAPPaige Miller, PharmD Candidate 2016

Patient Case• LC is a 76 yo WF who presented to Grant Memorial

Hospital on 11/13 with pain in her left hip and a left calf laceration resulting from a fall earlier that day.• Patient was hypotensive in the emergency department

with SBPs ranging from 67 to 82 mmHg. • Calf laceration had moderate bleeding.• She was taking dabigatran for chronic atrial fibrillation at

home.• Left hip X-ray revealed a left femur neck fracture.• Leukocytosis was also noted. • During transfer to Winchester Medical Center she

became hypotensive and was given norepinephrine.

Case: Labs on Arrival11/13

Blood Pressure (mmHg) 133/103

Heart Rate (bpm) 115Respiratory Rate (bpm) 22Temperature (°F ) 98.1WBC (k/cmm) 35.5HGB (gm/dL) 10.2HCT (%) 30.7

11/13Sodium (mMol/L) 142Chloride(mMol/L) 108BUN (mg/dL) 16Potassium (mMol/L) 4.3CO2 (mMol/L) 19.1SCr (mg/dL) 1.20BG (mg/dL) 159

• Height: 5’• Weight: 104 kg

• IBW: 45.5 kg

• DW: 68.9 kg• CrCl: 75.4 mL/min

Case• PMH pertinent for atrial fibrillation, CHF,

coronary artery disease (CAD), myocardial infarction, diabetes mellitus, ventricular tachycardia and venous stasis ulcer of lower extremity with recurrent cellulitis.

• Pertinent Home Medications: • Atenolol• Dabigatran• Digoxin• Furosemide• Hydrocodone-

acetaminophen• Losartan• Pravastatin• Prednisone

Allergies: baclofen, flu virus vaccine, tape

Case

• Treated for a urinary tract infection (UTI) on 10/29/15.

• Relevant Home Medication: Amoxicillin-clavulanate 500-125 mg: 1 tablet PO TID.

• Urine Culture taken on 11/13/15 showed no growth.

Case• Date of Intubation: 11/13/15• On 11/17 (Day 5 of Hospitalization) LC spiked

a fever and her WBC count started increasing • Labs began improving on 11/20 before

increasing again on 11/21• Extubation was attempted on 11/21, she

decompensated and was re-intubation on 11/22

Case: Relevant Labs11/17 11/18 11/19

Temperature (°F ) 99 100.7 100.8WBC (k/cmm) 15.1 17.5 19.6HGB (gm/dL) 7.8 7.1 9.0HCT (%) 22.4 20.9 26.2Platelet count (K/cmm)

132 149 154

Lymphocytes (%) 9.0 7.0 13.0Bands (%) 2 5 3Creatinine (mg/dL) 0.73 0.72 0.66BP (mmHg) 107/52 122/47 114/45

Case: Microbiology• Respiratory Culture (from endotracheal aspirate)

• Positive for Methicillin Resistant Staphylococcus aureus (MRSA) on 11/17, 11/21 and 11/23• Susceptible to : Linezolid (2), Rifampin (≤ 0.5),

Tetracycline (≤1), Trimeth/Sulfa (≤ 10), Vancomycin (1)• Resistant to: Nafcillin, Clindamycin

• Moderate growth Candida albicans on 11/17

• Blood Cultures (11/13, 11/18, 11/20, 12/01), Urine Cultures (11/13, 11/18, 11/23,12/01 ) and Fugal Culture (11/20) all showed no growth

• Vancomycin Trough 11/16 was 10.09 mg/L

Patient Case: Problem List

• Suspected sepsis with a hospital acquired organism

• Circulatory shock • Acute-on-chronic respiratory failure• Atrial fibrillation• Acute post hemorrhagic anemia• Lactic acidosis• Acute-on-chronic systolic congestive heart failure (CHF)• Comminuted fracture of the left hip

Case

Antibiotics

Strength

Frequency

Started

Stopped

Days of Therapy

Cefepime 2g IV Q12H 11/13 11/19 7Vancomycin

1000 mg IV Q24H 11/13 11/17 -

1250 mg IV Q24H 11/18 11/21 9 Zosyn ext. infusion

3.375 mg IV Q8H 11/19 11/29 11

Previous Inpatient Antibiotics Medications

Antibiotics Dose Frequency Start Date Stop DateLinezolid 600 mg IV BID 11/21 Current

Current Inpatient Antibiotics Medications

Case• Assessment:

1. Fever2. Increasing WBC count3. Intubated for ≥ 72 hours4. Respiratory Culture positive for MRSA

Ventilator Associated Pneumonia (VAP)1

• Common Causes1 • Aerobic gram-negative

bacilli • P. aeruginosa,

Escherichia coli, Klebsiella pneumoniae, and Acinetobacter species.

• Gram-positive cocci• Staphylococcus aureus

• Signs and Symptoms1

• Fever > 38° C (100.4°F),

• Leukocytosis or leukopenia

• Purulent secretions

VAP: pneumonia that develops more than 48-72 hours after endotracheal intubation1

VAP: Diagnosis1

• On Mechanical Ventilation for ≥ 48 to 72 hours +• New or progressive radiographic infiltrate in the

lung• Clinical Finding Suggestive of Infection:• Fever• Purulent Sputum• Leukocytosis• Decline in Oxygenation• Positive Respiratory Tract Cultures (options:

endotracheal aspirates, bronchoalveolar lavage [BAL] or protected specimen brush [PSB])

Initial Empiric VAP Treatment1

• Typically Cover for: • Streptococcus pneumoniae, Haemophilus

influenzae, Methicillin-sensitive Staphylococcus aureus, Sensitive gram negative bacilli (E. coli, K. pneumoniae, Enterobacter species, Proteus species, Serratia marcescens)

• If Concerned about MDR Pathogens cover for: • Pseudomonas aeruginosa, Klebsiella pneumoniae

(ESBL), Acinetobacter species, Legionella pneumophila and all previously listed bacteria

Initial Empiric VAP Treatment1

• Use: • Antipseudomonal cephalosporin or Antipseudomonal

carbepenem or β-lactam/β-lactamase inhibitor • Plus Antipseudomonal fluoroquinolone or

Aminoglycoside

• If risk factors for MRSA present add Linezolid or Vancomycin

• Reassess need for Empiric Therapy at (or before) Day 3

Treatment after Cultures Return

Positive for MRSA VAP

VAP MRSA Treatment2

• Vancomycin: 15-20 mg/kg/dose IV every 8-12 hours• Goal Trough for pneumonia: 15-20 mg/L• Monitor: renal function (SCr), trough, CBC with

differential• AE: red man syndrome, ototoxicity, nephrotoxicity,

phlebitis

• Linezolid: 600 mg PO/IV every 12 hours• Monitor: CBC with differential• AE: myelosuppression, visual impairment /

changes, serotonin syndrome, neuropathy

VAP MRSA Treatment2

• Treat for 7-21 days• Monitor resolution of infection: • Fever• CBC with differential• Chest X-ray• Cultures

Studies

Hamilton LA, et al. Treatment of methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or linezolid. J Trauma Acute Care Surg. 2012;72(6): 1478-83.

• Purpose: to determine the clinical success rate of high-dose vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) ventilator-associated pneumonia (VAP) in critically ill trauma patients.

• Retrospective, observational review of MRSA VAP patients seen in the ICU (trauma patients only) from January 1997 to December 2008 in Memphis, TN

• Demographics: age 41 ± 21, mainly male and Caucasian with APACHE II median score at admission = 18

Treatment of methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or linezolid.• Results: 125 patients with 141 episodes • 76 treated with vancomycin• 10 treated with linezolid• 55 switched from vancomycin to linezolid

• Clinical success was achieved in 88% (125 of 131)• 68/76 patients treated with Vancomycin only• 47/55 patients treated with Linezolid and Vancomycin

• VAP related mortality was 10% (12 of 125)• Conclusion: High dose vancomycin effective option

for the treatment of MRSA VAP in trauma ICU patients

Wunderink RG, et al. Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study. Clinical Infectious Diseases. 2012;54:621-9.

• Purpose: To provide a prospective analysis of the efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for the treatment of MRSA nosocomial pneumonia.

• Patients enrolled from October 2004 to January 2010. • General hospital patients• Randomized into two groups for 7 – 14 days

treatment: • 1) IV linezolid 600 mg Q12H• 2) IV vancomycin 15mg/kg Q12H (adjusted based on

trough levels)

Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study.

• Randomized: 1225 people• Allocated to linezolid: 618 mITT: 224 PP

population: 172• Allocated to vancomycin: 607 mITT: 224 PP

population: 176

• VAP patients: 221 of 348 (63.5%)• Linezolid 104 of 172• Vancomycin 117 of 176

• In the PP patients treated with linezolid 57.6% were clinically cured at the end of the study, compared to 46.6% in the vancomycin treatment group (P=0.042)

Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study.

• No difference between groups in development of anemia or thrombocytopenia or IT group 60 day mortality• Nephrotoxicity more common in vancomycin treatment

18.2% compared to 8.4% in the linezolid treatment group (based on laboratory evidence)

• Conclusion: Clinical response at the end of study was better with linezolid than vancomycin for the treatment of nosocomial pneumonia due to MRSA however there were no statistically significant differences in mortality between the two groups

Peyrani P, et al. Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study. Critical Care. 2014;18:R118.

• Purpose: Compare clinical success rates of patients treated with linezolid versus vancomycin for MRSA VAP.• Secondary Objective: Compare mortality, safety,

and resource utilization between the two groups• Mortality: all cause 14-day mortality after VAP diagnosis• Safety: Thrombocytopenia, Anemia, Nephrotoxicity• Resource Utilization: days on mechanical ventilation,

length of stay (LOS) in the ICU, LOS in the hospital

• Retrospective, observational study in ICU patients

Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study.

• Included in the analysis: 188 patients diagnosed with MRSA VAP• Linezolid: 101• Vancomycin: 87

• Clinical success reached in 85% of linezolid treated patients, 69% in vancomycin treated patients (p=0.009)

• Linezolid patients were 24% more likely to experience treatment success (p = 0.018)

• No difference in mortality (at 14 days), safety events or resource utilization between groups

• Conclusion: Patients with MRSA VAP are more likely to respond favorably to treatment with linezolid compared to those treated with vancomycin

Opinion• Patients treated with linezolid have better

clinical response than those treated with vancomycin

• Mortality benefit has yet to be seen in patients with an improved clinical response to linezolid

• Cost6Dose Unit Size AWP One Dose

Linezolid 600 mg IV 300 mL $750 $75Vancomycin

1000 mg IV

150 mL $86.98 $12.42

• Vancomycin Trough Level = ~ $1007

Case

• Extubated on 11/28. • Plan: • Continue Linezolid for 30 days (currently on Day 14).• Discharge tentatively planned for 12/5.

11/30 12/1 12/2Temperature (°F ) 98.2 97.3 100.2WBC (k/cmm) 13.8 13.8 13.5HGB (gm/dL) 9.6 9.6 9.6HCT (%) 29.6 29.4 29.4Platelet count (K/cmm) 272 274 244Lymphocytes (%) 9.0 19.6 16.8Bands (%) None

reportedNone reported

None reported

Creatinine (mg/dL) 0.80 0.80 0.77

References1. American Thoracic Society; Infectious Disease Society of America. Guideline for the management

of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. DOI: 10.1164/rccm.200405-644ST.

2. Lou C, Bayer A, Cosgrove SE, et al. Clinical practice guideline by the Infectious diseases society of America for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. Clinical Infectious Diseases. 2011; 52:285-92. DOI:10.1093/cid/ciq146.

3. Hamilton LA, Wood CG, Magnotti LJ, et al. Treatment of methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia with high-dose vancomycin or linezolid. J Trauma Acute Care Surg. 2012;72(6):1478-83.

4. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study. Clinical Infectious Diseases. 2012;54(5):621-9.

5. Peyrani P, Wiemken TL, Kelley R, et al. Higher clinical success in patients with ventilator-associated pnuemonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study. Critical Care. 2014;18:R118.

6. Red Book. Montvale, N.J.: Medical Economics Data; 2015. Micromedex. 7. James CW and Gurk-Turner CG. Recommendations for monitoring serum vancomycin

concentrations. Proc (Bayl Univ Med Cent). 2001;14(2):189-90. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1291340/.